JPH01139578A - 3-(1h-imidazol-1-yl)pyridazine derivative - Google Patents

Abstract

NEW MATERIAL:A 3-(1H-imidazol-1-yl)pyridazine derivative expressed by formula I [Y is 4-6C cyclic alkylamino or -Z-R which may contain Cl or hetero atom (Z is -NH-, =NCH3, -O-, -S- or =SO; R is 1-14C alkyl, 2-8C cyclic alkyl, allyl, 2-propynyl, 2-hydroxyethyl, naphthyl, naphthylmethyl, benzyl which may be optionally substituted by Cl, etc.)]. EXAMPLE:3-(1H-Imidazol-1-yl)-6-methylaminopyridazine. USE:Useful as an antithrombotic and antifungal agent, capable of exhibiting powerful activity against various fungi and having excellent drug effects and low toxicity. PREPARATION:For example, a 3-amino-6-chloropyridazine derivative expressed by formula II is reacted with imidazole to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Fields of Application] The present invention provides novel 3.
-(IH-·imidazol-1-yl)pyridazine derivative.

[Prior art] 6-[4-(IH-imidazol-1-yl)phenyl]-3(2H)-pyridazinone derivative (Japanese Patent Application Laid-Open No. 1986-
74679) is known to have antithrombotic and cardiotonic effects.

Also, Pharmazie, Volume 32,
555 (1977), it was reported that pyridazine derivatives have antibacterial effects.

However, 3-(IH-imidazol-1-yl)
There is no suggestion whatsoever regarding lidazine derivatives or their antithrombotic and antifungal effects.

[Problems to be Solved by the Present Invention] The purpose of the present invention is to improve the medicinal efficacy as an antithrombotic drug and an antithrombotic drug.
Our goal is to provide new compounds with excellent safety.

[Means for Solving the Problems] The present invention relates to 3-(IH-imidazol-1-yl) represented by the following -Momonen [I] and a lidazine derivative.

[In the formula, Y is C which may contain a chlorine atom or a petro atom
1 to C6 cyclic alkylamino group or formula -Z-R (wherein, Z represents -NH-1=NCHt, -0-1-8- or =S○, R is a C1 to C+a alkyl group , C2~
C6 cyclic alkyl group, allyl group, 2-provinyl group,
It means a 2-hydroxyethyl group, a naphthyl group, a naphthylmethyl group, a benzyl group that may be substituted with a chlorine atom, or a phenyl group that may be substituted with a chlorine atom or a lower alkyl group. ] In the general formula [I], Y specifically represents a chlorine atom, a methylamino group, an ethylamino group, a pro-ruamino group, a butylamino group, a pentylamino group, a hexylamino group, a peptylamino group, an octyl group. Amino group, nonylamino group,
Decylamino group, undecylamino group, dodecylamino group, tridecylamino group, tetradecylamino group, cyclohexylamino group, 2-hydroxyethylamino group,
benzylamino group, 2-chlorobenzylamino group, anilino group, N-benzyl-N-methylamino group, N-(2
,4-dichlorobenzyl)-N-methylamino group, N-
Methyl-N-naphthylmethyl) amino group, piperidino group, morpholino group, methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, peptyloxy group, octyloxy group, allyloxy group, 2 -provinyloxy group, phenoxy group, 2
゜4-Dichlorophenoxy group, methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group, hexylthio group, heptylthio group, octylthio group,
Phenylthio group, 4-chlorophenylthio group, 4-(t
ert-butyl) phenylthio group, 2-naphthylthio group, benzylthio group, 4-chlorobenzylthio group, methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, pentylsulfinyl group, hexylsulfinyl group, heptylsulfinyl group, Examples include octylsulfinyl group, benzylsulfinyl group, and 4-chlorobenzylsulfinyl group.

The compound of the present invention is shown below [Reaction formula-1, 2 and 3]
It can be easily manufactured by the following method.

[Reaction formula-1] [I1 co [1a
]c In the formula, Y is C4-C6 which may contain a heteroatom
represents a cyclic alkylamino group, or a formula -Z-R (wherein, Z represents -NH-5=NCHs, and R has the same meaning as above). That is, the above-mentioned compound [Ia] of the present invention can be obtained by reacting imidazole with a 3-amino-6-chloropyridazine derivative [I1] obtained by a known method according to Nippon Kagaku Zasshi, Vol. 82, 227 (1961). It can be manufactured by Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether, acetone, methyl ethyl ketone, and methyl isobutyl ketone. Ketone, N.
Examples include N-dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine, etc., or no solvent may be used, but it is preferable to use N,N-dimethylformamide. The reaction temperature is 60-200°C and the reaction time is 2-24 hours, but the reaction time is 3-24 hours at 120-160°C.
Preferably, this is carried out over a period of 5 hours. The ratio of compound m[ll] and imidazole used is usually 1 part of the former to 1 part of the latter.
~4 times the molar amount is used. In this reaction, inorganic bases such as sodium carbonate and potassium carbonate, triethylamine, and N are used.

A tertiary amine base such as N-dimethylaniline, a base such as sodium hydride, potassium tert-butoxy, etc. can be used, but it is preferable to use an excess of imidazole as the base.

[Reaction formula-2] [+11] [To] [Ic:Z
10-co [+d: Z is -9-1 [wherein Z represents 10- or -8-, and R has the same meaning as above] Step A In addition, the above-mentioned compound of the present invention [Ib ] can be produced by reacting the compound [+111 with a metal salt of imidazole. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, N, N, etc.
-dimethylformamide etc., but it is preferable to use dioxane. The reaction temperature is 0 to 100°C, and the reaction time is 2 to 10 hours.
Preferably it is carried out for 6 hours. Examples of the metal salt of imidazole include sodium salt, potassium salt, lithium salt, etc., but sodium salt is usually used. Compound [+1
1] and the metal salt of imidazole, it is preferable to use 1 to 1.2 times the mole of the latter to the former.

Step B Next, the compound [IC] of the present invention in which Z is 10- is
It can be produced by reacting compound f[lb] with an alkyl alcohol and a metal salt such as a phenol compound, furyl alcohol, or propargyl alcohol. Its metal salts include sodium salt, potassium salt,
Examples include lithium salts, but it is usually preferable to use sodium salts. As a reaction solvent, ethers such as tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, 1,N, N-dimethylformamide,
Examples include acetonitrile and alcohols corresponding to the metal salts. The reaction temperature is preferably 60 to 120°C and the reaction time is preferably 1 to 5 hours. Regarding the ratio of compound Ib and the metal salt used, the latter is used in a molar amount of 1 to 1.5 times that of the former. Further, the compound [Id] of the present invention in which Z is -S- can be produced by reacting the compound [Ib] with a metal salt of a thiol compound.

[Reaction formula-3] [+d co
[leco[wherein R has the same meaning as above. ]on the other hand,
The above-mentioned compound [Ie] of the present invention can be produced by reacting compound [ldl with m-chloroperbenzoic acid (m-CPBA) to cause an oxidation reaction. Examples of the reaction solvent used include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, benzene, etc., but it is usually preferable to use methylene chloride. It can be done in 1 to 4 hours, but
It is preferable to carry out the reaction at 0 to 10°C for 1 to 2 hours.

Compound *[The ratio of ldl and m-chloroperbenzoic acid used is 1 to 1. It is preferable to use twice the mole amount, preferably the same mole amount.

The compound [I] of the present invention exhibits anti-xW and antithrombotic effects, and has low toxicity, so it is useful as a prophylactic and therapeutic agent for mycosis, cerebral thrombosis, cerebral hypoembolism, peripheral arterial/venous occlusion, etc. It is. Therefore, ointments, jellies,
It can be used in external preparations such as creams, powders, solutions, emulsions or sprays, or tablets, granules, etc.
It is preferable to administer orally in the form of a solid preparation such as a powder or capsule. There is no particular difficulty in preparing these formulations, and they may be formulated according to known methods using excipients suitable for each. Examples of preferred excipients include the following. In the case of external preparations, for example, fatty acids, vegetable fats, paraffin, starch tragacanth, cellulose derivatives, silicone, silica, bentonite, talc,
Zinc oxide, lactose, aluminum hydroxide, calcium silicate, polyamide powder, water, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl carbonate, ethyl acetate,
Benzyl benzoate, glycerin, N.

Examples include N-dimethylformamide, glycerin formal, fatty acid esters of sorbitol, and chlorofluorohydrocarbons as Ila radicals. For solid preparations,
Examples include dextrose, sucrose, lactose, glucose, sodium chloride, gelatin, starch, magnesium stearate, talc, and animal/vegetable fats. The concentration of the compound of the present invention [I] in the external preparation is 0.
A range of 1 to 0.5% by weight is preferred. In addition, the oral dosage of the compound of the present invention [I] varies depending on age, body weight, and symptoms, but is usually about 50 to 1000 m/day for adults.
It can be increased or decreased as appropriate within the range of g.

Example 1 20°02g of 3-chloro-6-methylaminopyridazine
and imidazole (28.6 g'li) were dissolved in 30 ml of N,N-dimethylformamide, and the mixture was heated and stirred at 150° C. for 6 hours. After distilling off the solvent under reduced pressure, methylene chloride was added to the residue to dissolve it, washed with water, and dried. After drying under reduced pressure, the residue was recrystallized from ethanol to obtain 19.0 g (yield: 78%) of colorless prismatic crystals of 3-(IH-imidazol-1-yl)-6-methylaminopyridazine. Melting point 175-176
℃.

IRvQ day "cm-': 3250 (NH),
1610 (C=N) MS (m/z): 175 (M″″) Examples 2 to 23 The corresponding raw material compounds were treated in the same manner as in Example 1 to obtain the first.
The compounds shown in Tables 2 and 3 were obtained.

Table 1 Table 2 Table 3 Example 24 18 g of 60% sodium hydride in oil 200 ml of dry dioxane! A solution of 30 g of imidazole in 200 ml of dry dioxane was added dropwise to the turbid solution over 30 minutes, and the mixture was further heated and stirred at 100° C. for 2 hours. 59.6 g of 3,6-dichloropyridazine in 10 ml of dry dioxane under water cooling.
After dropping the t1 solution over 10 minutes, it was stirred at room temperature for 2 hours,
The mixture was further heated under reflux for 2 hours. Insoluble materials were collected by filtration, and dioxane was distilled off under reduced pressure.

300 ml of water was added to the residue and stirred, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol to give 37.5 g of colorless prismatic crystals of 3-chloro-6-(IH-imidazol-1-yl)pyridazine. (yield 52%). Melting point 1
83-184°C.

IRv” cm-’: 3 1
50 (CH).

1610 (C=N) MS (m/z): 180 (Ml) Example 25 After dissolving 0.42 g of sodium in 30 ml of allyl alcohol, 3-chloro-6-(IH-imidazole-1-
2.7 g of pyridazine was added and the mixture was heated under reflux for 2 hours. After cooling, insoluble matter was filtered off, and allyl alcohol was distilled off under reduced pressure. The residue was dissolved in methylene chloride, washed with water, and dried.
The solvent was removed under reduced pressure. The residue was recrystallized from ethanol-isopropyl ether to obtain 1.55 g (yield 51.2%) of 3-allyloxy-6-(1'H-imidazol-1-yl)pyridazine in the form of colorless needles. Melting point 113-1
14℃.

IRy;:j"cm-': 3080 (CH)
.

1 6 1 0 (C=N), MS
(m/z): 202 (M”).

Example 26 The corresponding starting compound was treated in the same manner as in Example 25 and recrystallized from dioxane-isopropyl ether to give colorless needle-like crystals of 3-(IH-imidazol-1-yl)-6-(2
-Provinyl)pyridazine 1.8 g (yield $60%) was obtained. Melting point: 216°C (decomposition point).

Example 27 60% sodium hydride in oil 0.96 g dry dioxane 50 ml 1 Fifl to n-octyl alcohol 3.1
After adding 2 g, 3.61 g of 3-chloro-6-(IH-imidazol-1-yl)pyridazine was added, and the mixture was heated under reflux for 2 hours. After cooling, insoluble materials were removed and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, washed with water, dried, and then dried under reduced pressure. The residue was recrystallized from isopropyl ether-petroleum ether to give colorless needle-like crystals of 3-(IH-imidazol-1-yl)-6-octyloxypyridazine 2.1
g (yield 38.3%) was obtained. Melting point 74-75°C.
IRvQ:ノ"cm-': 3 1 00 (C
H)+1610 (C=N) MS (m/Z): 274 (M”).

Example 28 The corresponding starting compound was treated in the same manner as in Example 27 and recrystallized from ethanol-ether to give colorless needle-shaped 3-(2
, 4-dichlorophenoxy)-6-(IH-imidazol-1-yl)pyridazine (2.3 g) was obtained. Melting point 169
~170℃.

Example 29 9.3 g of 28% methanol solution of sodium methoxide
and 4.32 g of n-butylmercaptan were dissolved in 100 ml of anhydrous methanol, and after heating and refluxing for 30 minutes, 7.22 g of 3-chloro-6-(IH-imidazol-1-yl)pyridazine was added. After refluxing for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, washed with water, dried, and then dried under reduced pressure.

The residue was recrystallized from ether-petroleum ether to give colorless needles of 3-butylthio-6-(IH-imidazole-1-
5.3 g (yield 66.7%) of pyridazine. Melting point 8
1-82℃.

IRv:,:j"cm-': 3100 (CH), 1
610 (C=N) MS (m/z): 234 (M”) Real IiI!
Examples 30-36 The corresponding starting compounds were treated in the same manner as in Example 29 to obtain the compounds shown in Table 4.

Table 4 Example 37 A solution of 3-1 methylthio-6-(IH-imidazol-1-yl) and 2.8 g of lidazine in 601 methylene chloride
A solution of 3 g of chlorobenzoic M in 40 ml of methylene chloride was added dropwise over 30 minutes while cooling with water.Then, the mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours, washed with a saturated aqueous sodium carbonate solution, washed with water, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-isopropyl ether to give 2.3 g of 3-butylsulfinyl-6-(IH-imidazol-1-yl)pyridazine as colorless needles (yield 76.7 %
) was obtained. Melting point 118-119°C.

IR:, 2j"cm-': 3130 (NH)+
1030<SO> MS (m/z): 250 (M').

Examples 38-41 The raw material compounds to be reacted were treated in the same manner as in Example 37 to obtain the compounds shown in Table 6.

Table 5 Formulation Example 1 Compound of the present invention 50 ff1g lactose
200 mg crystalline cellulose
40 ■ Magnesium stearate
5) The above mixture is mixed according to a conventional method and tableted to prepare tablets containing 50 rag of the active ingredient per tablet.

Formulation example 2 Compound of the present invention 50B milk ￥a
90mg corn starch
60I1g talc
30 mg Magnesium Stearate IOB The above mixture is granulated according to a conventional method to obtain granules.

Pharmacological experiment (1) Platelet aggregation inhibitory effect The platelet aggregation inhibitory effect of the compound of the present invention was demonstrated by bone (c, v,
g, Born) method [Nach + (Nature),
927-929 (+962)]. That is, citrated rabbit blood was collected and centrifuged to obtain plasma with a high platelet concentration (PRP) and blood Lt with a low platelet concentration (PPP). Next, 1.5μ of the test compound dissolved in dimethyl sulfoxide was added to PRP.
After adding 270μ and incubating for 1 minute at 37°C, arachidonic acid or collagen was added to induce aggregation. Platelet aggregation was measured using NKK Madracer, and the 50% inhibitory concentration (IC5oμm) of the test compound was determined from the concentration inhibition rate curve.

Note that aspirin was used as a control drug, and the results of representative examples are shown in Table 6.

Table 6 (2) Minimum Inhibitory Concentration (MlC) for Various Fungi Using a 911 constant Sabouraud dextrose medium, MIC was determined by the agar plate dilution method according to the standard method of the Japanese Society of Chemotherapy (revised in 1980). Note that clotrimazole was used as a control drug, and the results of representative examples are shown in Table 7.

Table 7 aX C, a, ): Candida 1lbicans IFo 1
060. (T, m,):)su] Tricho-phyton men
tagrophytes), (A, v,) Nearst 0 Tailma Versifier Oseichemy (Arthro
derma vanbreuseghemii)S'
l 7420゜b) CTZ: Clotrimazole (C! otrimazo
le).

(3) Acute toxicity test The test compound was suspended in 0.5% carboxymethyl cellulose solution, and DDY male mice weighing 20-25 g (1
Table 8 shows the results of 0 representative cases in which the 50% lethality t (LD50) was calculated from the cumulative mortality rate for 7 days after administration.

Table 8 [Effects of the Invention] The compound of the present invention showed stronger activity than aspirin in inhibiting platelet aggregation in vitro, and also showed activity comparable to clotrimazole in MIC measurement experiments against various fungi. Furthermore, it was confirmed to have low toxicity in animal experiments. The compound of the present invention is characterized by excellent effects as an antithrombotic agent or an antifungal agent.Patent applicant: Morishita Pharmaceutical Co., Ltd.

Claims (5)

[Claims] (1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, Y is C which may contain a chlorine atom or a hetero atom
_4 to C_6 cyclic alkylamino group or formula -Z-R(
In the formula, Z represents -NH-, =NCH_3, -O-, -S- or =SO. R is an alkyl group of C_1 to C_1_4, a cyclic alkyl group of C_2 to C_8, an allyl group, a 2-provinyl group, a 2-hydroxyethyl group, a naphthyl group, a naphthylmethyl group, a benzyl group that may be substituted with a chlorine atom or a phenyl group which may be substituted with a chlorine atom or a lower alkyl group. ). ] 3-(1H-imidazol-1-yl)pyridazine derivative. (2) The compound according to claim 1, wherein in the general formula [I], Y is the formula -Z-R, and Z is -NH-. (3) In the above general formula [I], when Y is the formula -Z-R and Z is =NCH_3, R is represented by a benzyl group or a naphthylmethyl group which may be substituted with a chlorine atom. A compound according to claim 1. (4) In the general formula [I], when Y is the formula -Z-R and Z is -O-, R is an alkyl group of C_1 to C_8, an allyl group, a 2-provinyl group, a phenyl group, or a chlorine group. A compound according to claim 1, which is represented by a phenyl group which may be substituted with an atom. (5) In the general formula [I], when Y is the formula -Z-R and Z is -S- or =SO, R is C_1 to C_
8, a naphthyl group, a benzyl group which may be substituted with a chlorine atom, or a phenyl group which may be substituted with a lower alkyl group.